Oral dosage forms of ketamine

ABSTRACT

The present invention relates to an oral dosage form for administration of ketamine and a method of preparing an oral dosage form for administration of ketamine, preferably once or twice a day.

This is the national stage of International ApplicationPCT/EP2015/058318, filed Apr. 16, 2015.

The present invention relates to an oral dosage form of ketamine and amethod of preparing said oral dosage form. The dosage form can be usedin the treatment of neuropathic pain, preferably once or twice a day.

Ketamine is a drug used in human and veterinary medicine, primarily forthe induction and maintenance of general anesthesia, usually incombination with a sedative. Other uses include sedation in intensivecare, analgesia, and treatment of bronchospasm. Ketamine has a widerange of effects in humans, including analgesia, anesthesia,hallucinations, elevated blood pressure, and bronchodilation. Like otherdrugs of its class, such as tiletamine and phencyclidine (PCP), ketamineinduces a state referred to as “dissociative anesthesia” and is used asa recreational drug. Ketamine hydrochloride is sold as Ketanest®,Ketaset®, and Ketalar®. Pharmacologically, ketamine is classified as anN-methyl-D-aspartate (NMDA) receptor antagonist.

Ketamine can be effective in treating depression in patients withdepression and bipolar disorder who have not responded toantidepressants. It produces a rapid antidepressant effect, as opposedto the several weeks taken by typical antidepressants to work.

Ketamine can also be effective in treating neuropathic pain. Neuropathicpain is pain caused by damage or disease that affects the somatosensorysystem. It may be associated with abnormal sensations calleddysesthesia, and pain produced by normally non-painful stimuli(allodynia). Neuropathic pain may have continuous and/or episodic(paroxysmal) components.

Central neuropathic pain is found in spinal cord injury, multiplesclerosis, and some strokes. Aside from diabetes and other metabolicconditions, the common causes of painful peripheral neuropathies areherpes zoster infection, HIV-related neuropathies, nutritionaldeficiencies, toxins, remote manifestations of malignancies, immunemediated disorders and physical trauma to a nerve trunk. Neuropathicpain is common in cancer as a direct result of cancer on peripheralnerves (e.g., compression by a tumor), or as a side effect ofchemotherapy, radiation injury or surgery.

At subanesthetic doses, ketamine produces a dissociative state,characterised by a sense of detachment from one's physical body and theexternal world which is known as depersonalization and derealization. Atsufficiently high doses, users may experience what is called the“K-hole”, a state of extreme dissociation with visual and auditoryhallucinations.

A problem connected to analgesics and opioid analgesics is the so-calleddose dumping. Dose dumping is a phenomenon that occurs, for instance,when patients do no comply with the advice to avoid the intake ofalcohol concomitantly with the administration of the controlled releasepharmaceutical dosage form. The intake of alcohol can acceleratedramatically the release of the active ingredient, thus leading topotentially very harmful consequences for the patient, in particular incase of analgesics and opioid analgesics. Further, the acceleratedrelease of the active ingredient by means of alcohol for example isoften also a desired process for people aiming at a hallucinogenicexperience caused by a high dose of the drug, thus leading to drugabuse.

It is therefore desirable to provide dosage forms that can minimize dosedumping and drug abuse.

Further, the possibility to form controlled release dosage forms ofketamine is described in the prior art. However, no specific controlledrelease composition or formulation comprising ketamine is known in theprior art. EP 1 103 256 A1 describes the use of ketamine in treatingneuroendocrine immune dysfunction or algogenic psychosyndrome. Theketamine can be administered orally, e.g. as a controlled release dosageform. WO 2008/134525 A1 is directed to deuterium labelled ketamine andpharmaceutical compositions thereof, also comprising release-controllingagents. DE 10 2007 009 888 A1 describes the use of S-(+)-ketamine fortreating depressions. It discloses i.a. its oral administration, withoutspecifying the composition or addressing the dose dumping problem and/ordrug abuse problem.

No specific controlled release composition or formulation comprisingketamine is described in the prior art and no controlled releaseformulation of ketamine has been marketed, but only ketamineformulations for parenteral administration, such as Ketanest, Ketasetand Ketalar, as no satisfactory in vivo plasma level of ketamine couldbe achieved with oral formulations.

It is therefore an object of the present invention to provide an oraldosage form of ketamine which provides a satisfactory in vivo plasmalevel of ketamine and at the same time prevents dose dumping and drugabuse.

The inventors of the present invention have now surprisingly found thatvery advantageous in vivo properties can be achieved by an oral dosageform comprising ketamine, which provides a specific in vitro release ofketamine.

Hence, one aspect of the present invention is the provision of an oraldosage form comprising ketamine or a pharmaceutically acceptable salt orsolvate thereof. In a first embodiment of the invention the dosage formprovides an in vitro release of ketamine of 0 to 40% after 2 hours, of10 to 70% after 4 hours, of 30 to 85% after 6 hours and of 45 to 100%after 8 hours, when measured according to the USP Basket Method I in0.1M HCl at 100 rpm and 37° C.

In a preferred embodiment, the in vitro release of ketamine is 5 to 30%,preferably 8 to 25% after 2 hours, 20 to 60% after 4 hours, 45 to 80%after 6 hours and 60 to 99% after 8 hours, when measured according tothe USP Basket Method I in 0.1M HCl at 100 rpm and 37° C.

A second aspect of the invention is a modified release oral dosage formcomprising ketamine or a pharmaceutically acceptable salt or solvatethereof, wherein the ratio of the amount of ketamine released after 1hour of in-vitro dissolution of the dosage form at 37° C. in a aqueoussolution containing 20% by volume of ethanol to the amount of ketaminereleased after 1 hour of in-vitro dissolution of the dosage form at 37°C. in an ethanol-free aqueous solution is less than 2:1, preferably lessthan 1.7:1, more preferably less than 1.5:1, most preferably less than1.2:1, when measured according to the USP 1 Basket Method in 0.1M HCl at100 rpm.

Hence, the dosage forms of the present invention have provenadvantageous to avoid the effect of so-called dose dumping. It has beenfound that the use of the dosage forms of the present invention is avery effective means to avoid or at least significantly reduce the riskof dose dumping upon ingestion of alcohol.

As used herein for all in vitro release measurements, the USP BasketMethod I is carried out in 500 ml liquid for ketamine amounts of lessthan or equal to 10 mg and in 1000 ml liquid for ketamine amounts ofmore than 10 mg. If ketamine is used as free base, the amount of 10 mgrefers to the weight of the free base. If ketamine is used in the formof a pharmaceutical acceptable salt or solvate, the amount of 10 mgrefers to the weight of the salt or solvate.

“Ketamine” as used herein is understood to comprise the compound offormula (I)

having the IUPAC name2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Accordingly,ketamine comprises the R and S enantiomers as well as pharmaceuticallyacceptable salts or solvates thereof. In one embodiment, ketamine is(R)-ketamine or pharmaceutically acceptable salts or solvates thereof.In another embodiment, ketamine is (S)-ketamine or pharmaceuticallyacceptable salts or solvates thereof. In a further embodiment, ketamineis a racemate of (S)-ketamine and (R)-ketamine or pharmaceuticallyacceptable salts or solvates thereof, or any mixture of (S)-ketamine and(R)-ketamine or pharmaceutically acceptable salts or solvates thereof.Ketamine can preferably comprise the pharmaceutically acceptable acidaddition salts thereof. The acids which are used to prepare thepharmaceutically acceptable acid addition salts are preferably thosewhich form non-toxic acid addition salts, i.e. salts containingpharmacologically acceptable anions, such as chloride, bromide, iodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, (D,L)- and L-tartrate, (D,L)- and L-malate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate andbenzoate. A preferred salt is the hydrochloride of ketamine.

Ketamine as used herein can also comprise its metabolites. Themetabolite is norketamine or dehydronorketamine, preferably norketamine.Norketamine has the IUPAC name2-amino-2-(2-chlorophenyl)cyclohexan-1-one of formula (II)

and is obtained from ketamine through N-demethylation. Norketamine canbe provided as (R)-norketamine or pharmaceutically acceptable salts orsolvates thereof, or (S)-norketamine or pharmaceutically acceptablesalts or solvates thereof, racemate of (S)-norketamine and(R)-norketamine or pharmaceutically acceptable salts or solvatesthereof, or any mixture of (S)-norketamine and (R)-norketamine orpharmaceutically acceptable salts or solvates thereof.Dehydronorketamine has the IUPAC name6-amino-6-(2-chlorophenyl)cyclohex-2-en-1-one of formula (III)

Dehydronorketamine can be provided as (R)-dehydronorketamine orpharmaceutically acceptable salts or solvates thereof, or(S)-dehydronorketamine or pharmaceutically acceptable salts or solvatesthereof, racemate of (S)-dehydronorketamine and (R)-dehydronorketamineor pharmaceutically acceptable salts or solvates thereof, or any mixtureof (S)-dehydronorketamine and (R)-dehydronorketamine or pharmaceuticallyacceptable salts or solvates thereof. Norketamine and dehydronorketaminecan preferably comprise the pharmaceutically acceptable acid additionsalts thereof. The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts are preferably those which form non-toxicacid addition salts, i.e. salts containing pharmacologically acceptableanions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, (D,L)- andL-tartrate, (D,L)- and L-malate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate and benzoate. A preferred salt is thehydrochloride salt.

The following description of embodiments applies for both aspects of theinvention. Further, the first aspect and the second aspect of theinvention are not mutually exclusive, i.e. embodiments of the firstaspect can at the same time comprise the features of the first aspectand vice versa.

The oral dosage form of the present invention is a modified releasedosage form. As used herein, the term “modified release” refers to adosage form in which the rate or place of release of the activeingredient is different from that of an immediate release dosage formwhen administered by the same route. Modified release dosage forms caninclude delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. The pharmaceutical compositions inmodified release dosage forms can be prepared using a variety ofmodified release devices including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof.

In one embodiment of the invention, the oral dosage form is a matrixcontrolled release dosage form.

In one embodiment, the matrix controlled release dosage form comprises amatrix system, which preferably is swellable, non-swellable, erodible ornon-erodible, and preferably comprises polymers, including syntheticpolymers, and naturally occurring polymers and derivatives, such aspolysaccharides and proteins. In a further embodiment, the dosage formcomprises a non-erodible matrix system. Ketamine can be dissolved ordispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered.

Preferred materials for forming a matrix comprise chitin, chitosan,dextran, and pullulan, gum agar, gum arabic, gum karaya, locust beangum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum,and scleroglucan, starches, such as dextrin and maltodextrin,hydrophilic colloids, such as pectin, phosphatides, such as lecithin,alginates, propylene glycol alginate, gelatin, collagen, andcellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC),carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC),hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP),cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose(HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid esters,polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid ormethacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.),poly(2-hydroxyethyl-methacrylate), polylactides, copolymers ofL-glutamic acid and ethyl-L-glutamate, degradable lactic acid-glycolicacid copolymers, poly-D-(−)-3-hydroxybutyric acid, and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

Additional materials for forming a matrix device comprise plastics, suchas polyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinylacetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethyleneterephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers; and fattycompounds, such as carnauba wax, microcrystalline wax, and triglyceridessuch as hydrogenated castor oil. In a preferred embodiment the matrixforming material is hydrogenated castor oil. In another preferredembodiment the matrix forming material is HPMC.

The matrix forming material is preferably present in the dosage form ofthe invention in a concentration of between 10 and 95 wt.-%, morepreferably 20 to 75%, in particular 25 to 65%, based on the total weightof the dosage form.

The dosage form comprising a matrix system may further compriseexcipients such as lubricants, fillers, glidants, binders, stabilizers.Regarding preferred embodiments of said excipients it is referred toexplanations given below.

In a preferred embodiment the dosage form comprises

and 95 wt.-%, more preferably 20 to 75%, in particular 30 to 65% matrixforming material,

0 to 90 wt.-%, preferably 5 to 70 wt. %, more preferably 10 to 50 wt. %,in particular 15 to 30 wt.-% fillers,

optionally 0 to 25 wt.-%, preferably 1 to 20 wt. %, more preferably 5 to15% binders,

0 to 5 wt.-%, preferably 0.1 to 4 wt. %, more preferably 0.5 to 3%glidants,

0 to 5 wt.-%, preferably 0.1 to 3 wt. %, more preferably 0.3 to 2%lubricants

based on the total weight of the dosage form.

The matrix controlled release dosage form can be prepared bydirect-compression, wet-granulation or dry-granulation. Directcompression is a preferred embodiment. For more detailed explanationsabout the compression step it is referred to the illustrations givenbelow.

In a further embodiment of the invention, the dosage form of theinvention can be present in form of an osmotic controlled releasedevice, including one-chamber system (elementary osmotic pump),two-chamber system (push-pull systems), asymmetric membrane technology(AMT), and extruding core system (ECS). Osmotic controlled releasedevices should comprise cores, for example tablets, comprising ketamine,which are enveloped by a semipermeable membrane which preferably has atleast one orifice. The water-permeable membrane is impermeable to thecomponents of the core but permits water to enter the system fromoutside by osmosis. The water which penetrates in then, through theosmotic pressure produced, releases the active ingredient in dissolvedor suspended form from the orifice(s) in the membrane. The total activeingredient release and the release rate can substantially be controlledvia the thickness and porosity of the semipermeable membrane, thecomposition of the core and the number and size of the orifice(s).

In addition to the ketamine, the core of the osmotic device optionallyincludes an osmotic agent which preferably creates a driving force fortransport of water from the environment of use into the core of thedevice.

In the osmotic two-chamber system, the core consists of two layers, oneactive ingredient layer and one osmosis layer. The active ingredientlayer preferably comprises 1 to 70% ketamine, 30 to 95% of one or moreosmopolymers. The osmosis layer preferably comprises 30 to 90% of one ormore osmopolymers, 10 to 60% of an osmogen, where the difference from100% in the individual layers is formed in each case independently ofone another by one or more additional ingredients in the form ofpharmaceutically usual excipients. The osmogens and osmopolymers used inthe core of the osmotic two-chamber system may be as described in thefollowing paragraphs.

In one embodiment, the osmotic agents are water-swellable polymers,which are also referred to as “osmopolymers” and “hydrogels,” includinghydrophilic vinyl and acrylic polymers, polysaccharides such as calciumalginate, polyethylene oxide (PEO), polyethylene glycol (PEG),polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate),poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP),crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVPcopolymers with hydrophobic monomers such as methyl methacrylate andvinyl acetate, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolate.

In a second embodiment, the osmotic agents are osmogens which arecapable of imbibing water to affect an osmotic pressure gradient acrossthe barrier of the surrounding coating. Preferred osmogens comprisewater-soluble salts of inorganic or organic acids or nonionic organicsubstances with a high solubility in water, such as for examplecarbohydrates, especially sugars, sugar alcohols or amino acids. Forexample, the osmogens are selected from inorganic salts such aschlorides, sulphates, carbonates and bicarbonates of alkali metals oralkaline earth metals, such as lithium, sodium, potassium, magnesium,calcium, and phosphates, hydrogen phosphates or dihydrogen phosphates,acetates, succinates, benzoates, citrates or ascorbates thereof. It isfurthermore possible to use pentoses such as arabinose, ribose orxylose, hexoses such as glucose, fructose, galactose or mannose,disaccharides such as sucrose, maltose or lactose or trisaccharides suchas raffinose. The water-soluble amino acids include glycine, leucine,alanine or methionine. Sodium chloride is particularly preferably usedaccording to the invention. The osmogens are preferably present in anamount of 10 to 30% based on the total mass of the core ingredients.

In one embodiment, a combination of osmogens and osmopolymers is used inthe osmotic controlled release device.

The core further comprises pharmaceutically acceptable excipientscomprising buffer substances such as sodium bicarbonate, binders such ashydroxypropylcellulose, hydroxypropylmethylcellulose and/orpolyvinylpyrrolidone, lubricants such as magnesium stearate, wettingagents such as sodiumlauryl sulphate and/or flow regulators such ascolloidal silicon dioxide.

Materials for forming the semipermeable membrane of the osmoticcontrolled release device include various grades of acrylics, vinyls,ethers, polyamides, polyesters, and cellulosic derivatives that arewater-permeable and water-insoluble at physiologically relevant pHs, orare susceptible to being rendered water-insoluble by chemicalalteration, such as crosslinking. Preferably, the material for formingthe semipermeable membrane comprises plasticized, unplasticized, andreinforced cellulose acetate (CA), cellulose diacetate, cellulosetriacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate(CAB), CA ethyl carbamate, CA phthalate, CA methyl carbamate, CAsuccinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturaland synthetic waxes.

In a further embodiment, the semipermeable membrane may also be ahydrophobic microporous membrane which is permeable to water vapor, asdisclosed in U.S. Pat. No. 5,798,119. Hydrophobic polymers for forminghydrophobic but water-permeable membranes comprise polyalkenes,polyethylene, polypropylene, polytetrafluoro-ethylene, polyacrylic acidderivatives, polyethers, polysulfones, polyethersulfones, polystyrenes,polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers,natural and synthetic waxes.

The delivery port(s) on the semipermeable membrane are formedpost-coating by mechanical or laser drilling. Alternatively, deliveryport(s) are formed in situ by erosion of a plug of water-solublematerial or by rupture of a thinner portion of the membrane over anindentation in the core. Yet further, delivery ports are formed duringthe coating process, as in the case of asymmetric membrane coatings.

The osmotic controlled release dosage form can be prepared according toconventional methods and techniques known to those skilled in the art(see Santus and Baker, J Controlled Release 1995, 35, 1-21; Verma etal., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Vermaet al., J Controlled Release 2002, 79, 7-27).

As described above, the dosage form disclosed herein can be an AMTcontrolled release dosage form, which comprises an asymmetric osmoticmembrane that coats a core comprising ketamine and otherpharmaceutically acceptable excipients or carriers. (See U.S. Pat. No.5,612,059 and WO 2002/17918.) The AMT controlled release dosage formscan be prepared according to conventional methods and techniques knownto those skilled in the art, including direct compression, drygranulation, wet granulation, and a dip-coating method.

In further embodiments, the dosage form disclosed herein is formulatedas ECS controlled release dosage form, which comprises an osmoticmembrane that coats a core comprising ketamine, hydroxylethyl cellulose,and other pharmaceutically acceptable excipients or carriers.

In a preferred embodiment of the invention, the oral dosage form is amulti particulate dosage form and comprises a multitude of particles.Particles may be pellets, granules, spheroids, microtablets. Preferably,particles are pellets which contain a core comprising ketamine or apharmaceutically acceptable salt or solvate thereof.

Preferably, the pellets contain a core comprising ketamine and a releasecontrol layer coated upon the core. Preferably, the release controllayer is (physically) separated from the ketamine containing core. Theketamine containing core may be a core which contains ketamine andexcipients. In those embodiments, the excipients preferably do notsubstantially retard or delay the release of the ketamine.

Preferably, the core comprises a layer of ketamine on an inert core. Theinert core (also referred to as seed core or neutral bead) may begranules or beads, preferably spherical, and further preferably madefrom sugar or cellulose or other suitable materials. By way of example,spherical inert cores based on saccharose, such as those commerciallyavailable under the trade name Suglets® or those based on cellulose,such as those commercially available under the trade name Celphere® orCellets® may be mentioned. Saccharose-based inert cores are particularlypreferred. Inert cores may preferably have a particle size in the rangeof 100 to 500 μm and more preferably in the range of 200 to 400 μm, withthe particle size range indicating the size range for 90% of theparticles as determined by sieve analysis.

Preferably, ketamine is provided by coating a ketamine-containing layerdirectly onto the inert cores. The ketamine-containing layer preferablydoes not delay release of ketamine, i.e. is an immediate-release layer.

In one embodiment, each pellet contains a core comprising ketamine and arelease control layer coated upon the core. In an alternativeembodiment, pellets containing ketamine cores and a release controllayer coated upon the cores can be mixed to other pellets.

In an embodiment of the invention, the core does not comprise a neutralbead as described above, but a bead comprising ketamine and optionallyat least one pharmaceutically acceptable excipient. The ketaminecontaining bead can be formed by dry granulation, wet granulation, spraygranulation or extrusion.

Preferably, a suitable ketamine-containing core comprises 10 to 50 wt.%, preferably 15 to 40 wt. %, more preferably 20 to 30 wt. % inert core(neutral bead),

20 to 90 wt. %, preferably 35 to 80 wt. %, more preferably 50 to 70 wt.% ketamine, in particular ketamine hydrochloride,

0.1 to 20 wt. %, preferably 1 to 15 wt. %, more preferably 3 to 10 wt. %binder, and optionally

0 to 20 wt. %, preferably 1 to 15 wt. %, more preferably 3 to 10 wt. %glidant,

based on the total weight of the ketamine containing core.

Binders generally serve to enhance the integrity and stability oftablets. In addition, they may improve the suitability of pharmaceuticalcompositions for granulation. Binders are commonly also used for thepreparation of films, such as active agent containing layers, around aninert core. Exemplary binders include synthetic polymers, such aspolyvinyl pyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate-copolymer,modified celluloses, such as hydroxy alkyl celluloses and mixturesthereof. A binder is typically used in an amount of 0 to 25% by weight,preferably 0.1 to 15% by weight and in further embodiments 1 to 10% byweight of the controlled release oral dosage form. Preferably,hypromellose (HPMC) or PVP is used as binder in the ketamine-containingcore, more preferably HPMC. Preferably, said HPMC has a methoxy contentof 20% to 40%, more preferably 25% to 35%. Further, preferably said HPMChas a hydroxypropoxy content of about 5% to 15%, more preferably 7% to12%. Preferably, a 2% by weight (aqueous) solution of said HPMC has aviscosity of 0.5 to 100 mPa·s, preferably 1 to 50 mPa·s, more preferably2 to 10 mPa·s, measured at 20° C., preferably by means of aBrookfield-Synchro-Lectric LVF viscosimeter. Preferably, the PVP has anaverage molecular weight of 1,000 to 2,500,000, preferably 5,000 to2,000,000, more preferably 10,000 to 1,500,000.

Generally, glidants such as disperse silica, such as Aerosil®, or talccan be used. In particular, talc is used as glidant in theketamine-containing core.

In one embodiment, the ketamine-containing core does not comprise aglidant.

The release control layer may be disposed in direct vicinity, i.e. inimmediate contact with and surrounding the ketamine containing core,which is preferred. In other exemplary embodiments, an intermediatelayer may be disposed between the ketamine containing core and therelease control layer. This intermediate layer may further control therelease of ketamine from the core. However, it is preferred that, ifpresent, the intermediate layer does not substantially influence therelease from the core.

The release control layer comprises a release control substance forcontrolling the release of ketamine from the pellets. The releasecontrol substance may be any substance known in the art as suitable tocontrol the release of an active substance. Exemplary embodiments ofsuitable control release substances include cellulose esters, such ascellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethyleneoxide, polylactide-co-glycolide and mixtures thereof. Further suitablepolymers include those selected from alkylcelluloses, in particularcellulose ethers, polymers and copolymers based on acrylate ormethacrylate, polymers and copolymers based on acrylic or methacrylicesters and mixtures thereof. Preferably, the release control substanceis a water insoluble polymer, preferably an alkyl cellulose. Morepreferably, the alkyl cellulose is ethyl cellulose.

In exemplary embodiments of the present invention wherein the releasecontrol substance is a polymer, said polymer has a weight averagemolecular weight of 5,000 to 500,0000 g/mol, preferably of 50,000 to900,000 g/mol, more preferably of 100,000 to 400,000 g/mol, for instanceof 140,000 to 300,000 g/mol. The weight average molecular weight ispreferably determined by gel permeation chromatography.

In further embodiments, and in addition or in the alternative to one ormore of the properties mentioned above, the release control substance,and in particular the polymer, preferably has a solubility in water ofless than 20 mg/l, preferably less than 15 mg/l, preferably between0.001 to 10.0 mg/l. The solubility in water is preferably determined inaccordance with European Regulation RL67-548 EWG, Annex V, Chapter A6(German version referred to and referenced herein).

In further embodiments where a polymer is used as or as part of therelease control substance, and in addition or in the alternative to oneor more of the properties mentioned above, the polymer has a glasstransition temperature of 20 to 220° C., for instance 60 to 150° C. or90 to 140° C. The glass transition temperature is preferably measured bymeans of differential scanning calorimetry DSC, preferably using aMettler Toledo instrument and a preferably applying a heating/coolingrate of 10° C. per minute.

In a particularly preferred embodiment the release-control substance isethylcellulose having an ethoxyl content of about 30 to 70%, morepreferred of about 40 to 60%. Preferably, a 2% by weight (aqueous)solution of ethylcellulose has a viscosity of 5 to 500 mPa·s, preferably10 to 100 mPa·s, measured at 25° C., preferably by means of aBrookfield-Synchro-Lectric LVF viscosimeter.

In exemplary embodiments, the release control substance is contained inan amount of 0.1 to 80% by weight of the total weight of the pellets inthe dosage form, more preferably in amounts of 0.5 to 60% by weight, 10to 50% by weight, 15 to 40% by weight, of the total weight of thepellets in the dosage form.

Control of the release rate can be adapted by appropriate selection ofthe control release substance or mixture of such substances, its/theiramount, coating thickness, inclusion of further excipients, such as poreformers and/or plasticizers or others.

Further to the release control substance, one or more additionalexcipients may be used, in particular in a release control layer. Apreferred excipient for use with the release control substance, inparticular a polymeric release control substance, is a plasticizerand/or a pore builder and/or glidants.

A plasticizer, as the term is used herein, is a substance that typicallylowers the glass transition temperature of the polymer it is used inadmixture with by at least 2° C., preferably at least 5° C., forinstance between 5 and 30° C., as compared to the polymer alone.Preferably, the plasticizer is triethyl citrate or propylene glycol.

A pore former usually is a substance having a water-solubility which ishigher than the water solubility of the release-control substance.Preferably, the pore former has a solubility in water of more than 20mg/l, preferably 50 mg/l to 5000 mg/l, more preferably 100 to 1000 mg/l.The solubility in water is preferably determined as described above. Inparticular, hydroxypropyl cellulose (HPC) is used as pore former.

In a preferred embodiment, the release control layer comprises

20 to 95 wt. %, preferably 40 to 80 wt. %, more preferably 50 to 70 wt.% release control substance, preferably as described above,

0.1 to 30 wt. %, preferably 1 to 25 wt. %, more preferably 5 to 20 wt. %pore builder, preferably as described above,

0.1 to 30 wt. %, preferably 1 to 25 wt. %, more preferably 5 to 20 wt. %plasticizer,

preferably as described above, and optionally

0 to 40 wt. %, preferably 3 to 30 wt. %, more preferably 5 to 20 wt. %glidant, preferably

as described above,

based on the total weight of the release control layer.

The release control layer may be a single layer or a plurality oflayers. For ease of fabrication, embodiments with a single releasecontrol layer are preferred.

The pellets may be used as a pharmaceutical formulation, for instance,without any further processing. For this kind of administration, thepellets are preferably filled into sachets. In the alternative, they maybe incorporated into capsules, optionally together with one or moreexcipients, or into other suitable ingestible pharmaceutical dosageforms.

Most preferably, the pellets are contained in an external phase of atleast one pharmaceutically acceptable excipient. Furthermore, thecontrolled release oral dosage form is preferably a tablet.

As evident from what has been set out before, most preferably, the oraldosage form according to the present invention does not contain anyketamine in immediate-release form, i.e. does not contain ketamine, therelease of which is not controlled by the release-control substance(s).For instance, a tablet comprising the plurality of controlled releaseketamine pellets does not comprise any further ketamine in the externalphase or as top-coating on the tablet.

In particularly preferred embodiments, the pellets are mixed to aso-called “external phase” in order to be compressed into tablets. Theexternal phase should ensure the stability of the pellets during thecompression and is usually composed of one or more pharmaceuticallyacceptable excipients, such as fillers, binders, disintegrants, glidantsand lubricants.

Fillers are normally used to dilute a pharmaceutical composition andprovide bulk. Examples for preferred fillers include lactose, starch,calcium phosphate, calcium carbonate, saccharose, sugar alcohols such asmannitol, sorbitol, xylitol, and celluloses and derivatives.Microcrystalline cellulose is particularly preferred.

In a preferred embodiment a filler mixture comprising sodiumcarboxymethyl cellulose and microcrystalline cellulose, preferably in aweight ratio of 5:1 to 1:5, more preferably 3:1 to 1:3 is used. A filleror mixture of fillers may be used in an amount of 0 to 80% by weight,preferably 1 to 70% by weight, based on the total weight of thecontrolled release oral dosage form, preferably the tablet.

Binders generally serve to enhance the integrity and stability oftablets. In addition, they may improve the suitability of pharmaceuticalcompositions for granulation. Binders are commonly also used for thepreparation of films, such as active agent containing layers, around aninert core. Exemplary binders include synthetic polymers, such aspolyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate-copolymer,modified celluloses, such as hydroxy alkyl celluloses and mixturesthereof. A binder is typically used in an amount of 0 to 30% by weight,preferably 0.1 to 15% by weight and in further embodiments 1 to 10% byweight of the controlled release oral dosage form. Preferablyhypromellose (HPMC) is used as binder.

A disintegrant enhances the disintegration of a dosage form, inparticular a tablet, after its immersion in water or gastric juices.Suitable disintegrants include carrageenan, starchs, croscarmellose,crospovidone and mixtures thereof. Disintegrants may be used in amountsof 0 to 25% by weight, preferably 1 to 20% by weight and in furtherembodiments 3 to 15% by weight of the controlled release oral dosageform, preferably the tablet.

The oral dosage forms may further include a glidant, such as dispersesilica, such as Aerosil®, or talc. A glidant (or mixture thereof) may becomprised in an amount of 0 to 5% by weight, for instance 0.1 to 4% byweight of the controlled release oral dosage form, preferably thetablet.

The oral controlled release dosage form may further comprise alubricant, in particular in tablets prepared by compression. Suitablelubricants include stearic acid, magnesium stearate, adipic acid andsodium stearyl fumarate (Pruv®).

Preferably, the amount of pellets in the controlled release oral dosageform ranges from 1% to 100% by weight, based on the total weight of thecontrolled release dosage form. In preferred embodiments, the pelletsare comprised in an amount of 20% to 90% by weight, more preferably 25%to 80% by weight, based on the total weight of the controlled releasedosage form.

In a preferred embodiment the external phase (without coated cores)comprises

85 to 99.9%, preferably 90 to 98% by weight filler,

0 to 5%, preferably 0.1 to 1.0% by weight lubricant and

0.1 to 10%, preferably 1.0 to 5% by weight glidant,

based on the total weight of the external phase.

Optionally, the oral dosage form according to the present invention,particularly when present in the form of a tablet, can comprise anexternal film for improved ease of swallowing, for protection, forcolouring, for taste-masking or other purposes. Preferably, thisexternal film does not influence the release of ketamine to anysignificant extent. The external film may comprise the usual excipientsknown in this art for this purpose. A combination of hypromellose, talc,a colouring agent, such as titanium dioxide, and/or a polymer, such aspolyethylene glycol is a preferred embodiment herein. Preferably, readyto use products like Opadry® based on hypromellose or polyvinyl alcoholare used for the film coating. This optional film is not counted towardsthe total weight of the controlled release oral dosage form herein.Expressed differently, any amount of an ingredient expressed as weightpercent herein refers to the controlled release oral dosage form withoutthis optional external film. As evident from the above, the externalfilm is free of ketamine in any form.

The oral dosage form according to the present invention has theadvantage that it may be divided into two or more units withoutimpairing the controlled release of ketamine. The controlled releaseoral dosage form, and in particular the tablet, may therefore comprisemeans facilitating its division into two or more units, such as abreak-line, each of said units providing controlled release of ketamine.The dosage form according to the present invention therefore providesfor the possibility to adjust the dosage, for instance halve the dosageby breaking the tablet in two.

In preferred embodiments according to the present invention, theketamine salt is ketamine hydrochloride. The dosage form may containketamine in amounts of 5 to 400 mg, preferably 5 to 200 mg. If ketamineis used as free base, the amount of 5 to 400 mg refers to the weight ofthe free base. If ketamine is used in the form of a pharmaceuticalacceptable salt, the amount of 5 to 400 mg refers to the weight of thesalt. Preferably, the dosage form of the present invention comprises 10mg ketamine, 20 mg ketamine, 40 mg ketamine, 80 mg ketamine, 100 mgketamine, 120 mg ketamine, 140 mg ketamine, 160 mg ketamine, 180 mgketamine, 200 mg ketamine, 220 mg ketamine, 240 mg ketamine, 260 mgketamine, 280 mg ketamine, 300 mg ketamine, 320 mg ketamine, 340 mgketamine, 360 mg ketamine, 380 mg ketamine, more preferably 10 mgketamine hydrochloride, 20 mg ketamine hydrochloride, 40 mg ketaminehydrochloride, 80 mg ketamine hydrochloride, 100 mg ketaminehydrochloride, 120 mg ketamine hydrochloride, 140 mg ketaminehydrochloride, 160 mg ketamine hydrochloride, 180 mg ketaminehydrochloride, 200 mg ketamine hydrochloride, 220 mg ketaminehydrochloride, 240 mg ketamine hydrochloride, 260 mg ketaminehydrochloride, 280 mg ketamine hydrochloride, 300 mg ketaminehydrochloride, 320 mg ketamine hydrochloride, 340 mg ketaminehydrochloride, 360 mg ketamine hydrochloride, 380 mg ketaminehydrochloride.

It is further preferred that the dosage form of the present inventioncomprises:

-   i) ketamine-containing cores comprising    -   1 to 30 wt. %, preferably 2 to 20 wt. %, more preferably 3 to 10        wt. % inert cores,    -   1 to 40 wt. %, preferably 5 to 20 wt. %, more preferably 10 to        15 wt. % ketamine,    -   in particular ketamine hydrochloride,    -   0.01 to 10 wt. %, preferably 0.1 to 5 wt. %, more preferably 0.5        to 3 wt. % binder,    -   and    -   0 to 10 wt. %, preferably 0.1 to 5 wt. %, more preferably 0.5 to        3 wt. % glidant,-   ii) a release-control layer coated on each ketamine-containing core,    comprising    -   1 to 40 wt. %, preferably 3 to 20 wt. %, more preferably 7 to 15        wt. % release-control substance,    -   0.01 to 10 wt. %, preferably 0.1 to 6 wt. %, more preferably 1        to 4 wt. % pore builder,    -   0 to 10 wt. %, preferably 0.1 to 6 wt. %, more preferably 1 to 4        wt. % plasticizer,    -   0 to 15 wt. %, preferably 0.1 to 10 wt. %, more preferably 0.5        to 5 wt. % glidant,        and-   iii) an external phase comprising    -   20 to 85%, preferably 40 to 75%, more preferably 50 to 65%        filler,    -   0 to 3 wt. %, preferably 0.001 to 2.0 wt. %, more preferably 0.1        to 0.5 wt. % lubricant and    -   0 to 5 wt. %, preferably 0.1 to 5 wt. %, more preferably 0.5 to        2.0 wt. % glidant,        wherein all wt. % are based on the total weight of the tablet        (without film coating).

The tablets of the present invention preferably have a tablet height of2 to 8 mm, more preferably 3 to 5 mm, and a length of 3 to 22 mm,preferably 5 to 17 mm. Preferably, the tablets have a hardness of 40 to300 N, more preferably of 50 to 200 N.

In a further embodiment of the invention, the administration of a singleoral dosage form leads in-vivo to a C_(max) of ketamine of 1 to 150ng/ml, preferably 2 to 120 ng/ml, more preferably 3 to 100 ng/ml, stillmore preferably 4 to 70 ng/ml, further more preferably 5 to 40 ng/ml,and to a AUC_(0-∞) of 5 to 1000 h·ng/ml, preferably 10 to 750 h·ng/ml,more preferably 50 to 600 h·ng/ml, still more preferably 100 to 400h·ng/ml.

In a further embodiment, the administration of a single oral dosage formleads in-vivo to a C_(max) of norketamine of 5 to 750 ng/ml, preferably10 to 600 ng/ml, more preferably 15 to 500 ng/ml, still more preferably20 to 400 ng/ml, further more preferably 25 to 300 ng/ml, and to aAUC_(0-∞) of 100 to 8000 h·ng/ml, preferably 150 to 6000 h·ng/ml, morepreferably 500 to 4000 h·ng/ml.

“C_(max)” means the peak concentration of ketamine in the plasma, e.g.determined as described below. “AUC_(0-∞)” describes ketaminebioavailability and is measured by calculating the area under curve(AUC) of the plasma drug concentration time profile from time zeroextrapolated to infinity.

In a further preferred embodiment of the invention, T_(max) of ketamineis 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, mostpreferably 5 to 7 h.

In a further preferred embodiment of the invention, T_(max) ofnorketamine is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h,most preferably 5 to 7 h.

“T_(max)” means the time from administration to reach C_(max).

In a further preferred embodiment of the invention, the oral dosage formhas a F_(abs) of 5 to 25%, preferably 7 to 20%, more preferably 9 to18%.

“F_(abs)” is the absolute bioavailability. Absolute bioavailabilitycompares the bioavailability of the active drug in systemic circulationfollowing non-intravenous administration (i.e., after oraladministration in the present case), with the bioavailability of thesame drug following intravenous administration. It is the fraction ofthe drug absorbed through non-intravenous administration compared withthe corresponding intravenous administration of the same drug. Theabsolute bioavailability is the dose-corrected area under curve (AUC)non-intravenous (oral) divided by AUC intravenous. For example, theformula for calculating F_(abs) for a drug administered by the oralroute is given below:F _(abs)=AUC_(oral)/AUC_(iv)×dose_(iv)/dose_(oral)

The controlled release oral dosage forms according to the presentinvention are preferably for use in the treatment of severe and verysevere pain, more preferably of severe and very severe paincorresponding to a value of between 6 and 10 according to the visualanalogue scale (VAS) numeric pain distress scale of 1 to 10. Inparticular, the controlled release oral dosage form is suitable forpatients who need continuous treatment over an extended period of time.

The controlled release oral dosage forms according to the presentinvention are preferably for use in the treatment of neuropathic pain.As described above, neuropathic pain is found in spinal cord injury,multiple sclerosis, and some strokes. Aside from diabetes and othermetabolic conditions, the common causes of painful peripheralneuropathies are herpes zoster infection, HIV-related neuropathies,nutritional deficiencies, toxins, remote manifestations of malignancies,immune mediated disorders and physical trauma to a nerve trunk.Neuropathic pain is common in cancer as a direct result of cancer onperipheral nerves (e.g., compression by a tumor), or as a side effect ofchemotherapy, radiation injury or surgery.

Accordingly, the oral dosage form of the present invention is preferablyfor use in the treatment of patients suffering from spinal cord injury,multiple sclerosis, cancer, immune mediated disorders, metabolicconditions such as diabetes, herpes zoster infection, HIV-relatedneuropathies, nutritional deficiencies.

Further, the present invention provides a method for treating severe andvery severe pain, more preferably of severe and very severe paincorresponding to a value of between 6 and 10 according to the visualanalogue scale (VAS) numeric pain distress scale of 1 to 10, using anoral dosage form of ketamine as described above.

In a further embodiment, a method for treating depression in patientswith depression and bipolar disorder who have not responded toantidepressants is provided.

Yet further, a method of treating neuropathic pain is provided using anoral dosage form of ketamine as described above.

In an embodiment of the invention, a method of treating patientssuffering from spinal cord injury, multiple sclerosis, cancer, immunemediated disorders, metabolic conditions such as diabetes, herpes zosterinfection, HIV-related neuropathies, nutritional deficiencies using theoral dosage form of the present invention is disclosed.

The oral dosage form of the present invention is administered once ortwice daily, preferably twice daily.

According to a further aspect, the present invention provides a methodfor preparing an oral dosage form, preferably as described above,comprising:

-   a) coating each inert core with a layer comprising ketamine or a    pharmaceutically acceptable salt or solvent thereof,-   b) coating each coated inert core with a release control layer    comprising a release control substance for controlling the release    of ketamine, thus forming pellets,-   c) mixing the pellets with at least one pharmaceutically acceptable    excipient,-   d) forming a tablet from the mixture comprising the pellets and the    at least one pharmaceutically acceptable excipient.

For preferred embodiments of inert cores, preferred ketamine forms,release controlling substances, further excipients, the pellets etc., itis referred to the explanations concerning embodiments of the dosageforms of the present invention above, which naturally equally apply tothe method for preparing a controlled release dosage form according tothe present invention.

Step a) may further include dissolving or suspending ketamine or a saltthereof in a suitable solvent or solvent mixture, optionally togetherwith a binder, such as a hydroxyalkyl cellulose, such as hydroxypropylmethyl cellulose. The solvent is preferably water, an alcohol,such as ethanol, or mixtures thereof.

Preferably, the inert cores are sugar spheres. Preferably, ketaminehydrochloride is used. Further preferably, the coating step a) is acoating step in a fluid bed processor wherein preferably a solution orsuspension (in particular solution) of ketamine hydrochloride and one ormore excipients, such as hypromellose, is sprayed onto the inert cores.The coating solution or suspension usually comprises respectivelyconsists of water and/or an alcohol. Preferably, the process temperatureis between 30 and 60° C.

Preferably, step b) involves coating by spraying a coating solutioncontaining the release control substance onto the coated inert coresfrom step a). The spraying step is preferably performed in a fluid bedprocessor. The fluid bed processor is preferably suitable for coatingpowders, particles, inert spheres, beads and tablets, and/orsimultaneous drying. Preferably, the process temperature is between 30and 60° C.

The solvent of the coating solution or suspension from step b)predominantly contains alcohol, i.e. the solvent used for dissolving therelease controlling agent and optional further excipients containspreferably 60% or more by weight, more preferably 70% or more by weightof alcohol. A mixture of ethanol and water is particularly preferred.Furthermore, preferably ethylcellulose is used as the releasecontrolling agent. Additional excipients may include hydroxypropylcellulose, talc, triethyl citrate and other pharmaceutically suitableexcipients.

The pellets preferably have a weight average particle diameter (d₅₀) of50 to 1000 μm, in preferred embodiments 100 to 800 μm, in furtherembodiments 150 to 600 μm, as measured by sieve analysis, such as bymeans of a Retsch Siebmaschine AS 300 control. The thickness of therelease control layer is preferably in a range of 0.1 to 200 μm,preferably 0.5 to 100 μm.

Tablets with a combination of several of the above features have beenfound to be particularly advantageous: they provide good clinicalefficacy, not least due to providing an advantageous dissolution profilewithout the need to include an immediate release portion of ketamine.They can be broken or divided without affecting the release of drug fromthe tablet. Dose dumping phenomena do not occur.

The invention will be further described by way of exemplary embodimentswith reference to the Figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles of a 20 mg containing ketaminehydrochloride tablet in 0.1M HCl and of a 20 mg containing ketaminehydrochloride tablet in HCl/EtOH 80:20;

FIG. 2a shows the geometric mean curves of (±)-ketamine after i.v.infusion of 5 mg (within 0.5 h) and oral administration of 10, 20, 40and 80 mg ketamine modified release tablets according to the invention;

FIG. 2b shows the geometric mean curves of (±)-norketamine after i.v.infusion of 5 mg (within 0.5 h) and oral administration of 10, 20, 40and 80 mg ketamine modified release tablets according to the invention.

EXAMPLES Example 1: Preparation of Matrix Controlled Release TabletsContaining 20 mg Ketamine Hydrochloride

Ketamine HCl 20.00 mg Hydrogenated castor oil 92.74 mg Microcrystallinecellulose 35.00 mg Aerosil 200 1.50 mg Magnesium stearate 0.76 mg Totaltablet 150.00 mg

Ketamine HCl, hydrogenated castor oil, microcrystalline cellulose andAerosil 200 are sieved through a 600 μm sieve and mixed for 10 minutes.

Magnesium stearate is added to the mixture and further mixed for 2minutes. Tablets with the composition outlined in the table above arepressed on a rotary machine with oblong punches.

Example 2: Preparation of Multi-Particulate Tablets Containing 20 mgKetamine Hydrochloride

Step 1:

A spraying solution is prepared from the following ingredients:

Hypromellose 3.00 kg Ketamine hydrochloride 20.00 kg  Sugar spheres 8.00kg Ethanol 96% q.s. Water, purified q.s.

A spraying suspension is prepared by successively dissolvinghypromellose and ketamine hydrochloride in a mixture of purified waterand ethanol.

Sugar spheres (saccharose, particle size range (90%) 200 to 400 μm) arefilled into a fluid-bed processor with a bottom-spray nozzle andpre-heated. The spraying suspension is then sprayed onto the sugarspheres in the fluid-bed processor, thus preparing a plurality of sugarspheres having a layer of ketamine coated thereupon. The coated sugarspheres are then sieved to remove agglomerates (vibration sieve orequivalent).

Step 2:

A coating suspension is prepared from the following ingredients:

Ethylcellulose 14.54 kg  Hydroxypropyl cellulose 4.00 kg Triethylcitrate 3.27 kg Talc 1.45 kg Ethanol 96% q.s Water, purified q.s

Hydroxypropyl cellulose is dissolved in water. Ethylcellulose andethanol are then added to the solution. Finally, triethyl citrate andtalc are added and the solution is continuously stirred.

The coated sugar spheres from Step 1 are filled into a fluid-bedprocessor and preheated. The coated solution prepared as indicated aboveis sprayed onto the coated sugar spheres. The pellets obtained therebyas then sieved to remove the agglomerates.

Step 3:

The following ingredients are dry mixed to a blend:

Pellets from Step 2 54.26 kg Carmellose sodium 46.00 kg Microcrystallinecellulose 55.49 kg Colloidal anhydrous silica  1.50 kg Magnesiumstearate  0.75 kg

The resulting dry blend is then compressed to tablets.

Step 4 (Optional):

A tablet coating suspension is made from the following ingredients:

Opadry ® II White 1.20 kg Water, purified q.s

31.6 kg tablets are film coated with the tablet coating suspension.

The dissolution profiles of the 20 mg tablets are in accordance with thepresent invention, as apparent from FIG. 1. The dissolution profileswere measured using the USP 1 Basket Method at 37° C., 1000 ml 100 rpmin 0.1M HCl and HCl/EtOH 80:20.

Example 3: In Vivo Pharmacokinetics

A comparative bioavailability study of ketamine and norketamine aftersingle dose administration of ketamine (in form of ketaminehydrochloride) 10, 20, 40 and 80 mg modified release tablets accordingto the invention in fasting state and 5 mg ketamine (in form of ketaminehydrochloride) solution for infusion was carried out. In the study, theC_(max), F_(abs), AUC_(0-∞), and T_(max) as described above aredetermined in vivo in healthy subjects.

The modified release tablets have been produced in analogy to Example 2.

Objectives

Single dose, open label, five-treatment, five-period, consecutive studywith at least 7 days wash-out between the study periods.

In the first treatment all subjects received a single dose of 5 mg(±)-ketamine solution for infusion within 30 min intravenously infasting state.

The orally administered single doses of (±)-ketamine modified releasetablets were given in consecutively increasing doses of 10, 20, 40 and80 mg with 240 ml of table water in fasting state.

(±)-Ketamine and (±)-norketamine were measured in serum, urine and feces

Number of Subjects, Main Criteria for Inclusion

-   -   15 analyzed    -   age: 18-45 years    -   sex: male and female    -   ethnic origin: Caucasian    -   body mass index: ≥18.5 kg/m² and ≤30 kg/m²    -   good health as evidenced by the results of the clinical        examination, ECG, and the laboratory check-up, which were judged        by the clinical investigator not to differ in a clinical        relevant way from the normal state    -   heart frequency between 50 and 90 bpm    -   blood pressure between 140 and 100 systolic and 90 and 60        diastolic    -   written informed consent        Sampling

-   Blood: blank, 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.5, 2, 3, 4, 6,    8, 12, 24 h after intravenous administration and blank, 0, 0.5, 1,    1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 h    after oral administration

-   Urine: 0-24 h, 24-48 h and 48-72 h

-   Feces: 0-120 h    Drug Assay

Validated achiral LC-MS/MS method for (±)-ketamine and (±)-norketamine,performed in a laboratory certified according to GLP (Good LaboratoryPractice)

Pharmacokinetic Results

The results are summarized in the following tables, wherein AUC_(0-∞)stands for the area under the curve from zero extrapolated to infinity,C_(max) stands for the maximum plasma concentration, T_(max) stands forthe time to C_(max), F_(abs) stands for absolute bioavailability,T_(1/2) stands for the apparent terminal half-life.

TABLE 1 Pharmacokinetic characteristics of (±)-ketamine afterintravenous infusion (30 min) of 5 mg (±)-ketamine and oraladministration of 10, 20, 40 and 80 mg ketamine PR tablets 5 mg i.v. 10mg 20 mg 40 mg 80 mg AUC_(0-∞) ng × h/ml 59.9 ± 13.2 13.5 ± 9.73 27.1 ±21.9 75.6 ± 48.3 178 ± 145 C_(max) ng/ml 33.7 ± 9.74  1.48 ± 0.901 3.25± 2.29 7.64 ± 4.69 16.7 ± 13.4 T_(max) h — 4.87 ± 1.22  5.87 ± 0.64* 6.00 ± 0.76*  6.07 ± 0.26* F_(abs) % — 11.5 ± 8.09 11.0 ± 8.57   15.9 ±9.53*^(†)   17.9 ± 12.3*^(†) T_(1/2) h 6.99 ± 5.22 7.39 ± 4.86 6.09 ±4.98  8.44 ± 1.54^(#†)  8.89 ± 1.42^(#†) ^(#)vs. 5 mg i.v., *vs. 10 mg,^(†)vs 20 mg

TABLE 2 Pharmacokinetics of (±)-norketamine after intravenous infusion(30 min) of 5 mg (±)-ketamine and oral administration of 10, 20, 40 and80 mg ketamine PR tablets 5 mg 10 mg 20 mg 40 mg 80 mg AUC_(0-∞) ng ×h/ml 87.7 ± 24.1  162 ± 39.7 339 ± 100 653 ± 164 1620 ± 731  C_(max)ng/ml 11.4 ± 2.85 13.4 ± 2.92 27.6 ± 6.62 48.7 ± 10.4 113 ± 53.0 T_(max) h 0.93 ± 0.32 4.72 ± 1.02  5.33 ± 0.77*  5.67 ± 0.52*  6.10 ±0.60*^(†‡) T_(1/2) h 8.01 ± 2.35 7.38 ± 1.63 7.74 ± 3.09  8.25 ±2.70^(†) 8.48 ± 1.56* *vs. 10 mg, ^(†)vs 20 mg, ^(‡)vs. 40 mg, p < 0.05(Wilcoxon test)

The maximum concentration (C_(max)) and the time of maximumconcentration (T_(max)) were obtained directly from the measuredconcentration-time curves.

The area under the concentrations-time curve (AUC0-t) was calculatedwith the measured data points from the time of administration until thelast quantifiable concentration by the trapezoidal formula. The AUC wasassessed up to the last sampling time above the limit of quantificationand is extrapolated to infinity to obtain the AUC_(0-∞) values.

Apparent Terminal half-life (T_(1/2)) was calculated by the followingequation T_(1/2)=ln2/λ_(z). The terminal elimination rate constant(λ_(z)) was evaluated from the terminal slope by log-linear regressionanalysis.

The absolute bioavailability (F_(abs)) was calculated by the followingequationF _(abs)=AUC_(oral)/AUC_(iv)×dose_(iv)/dose_(oral).

The invention claimed is:
 1. An oral dosage form comprising ketamine ora pharmaceutically acceptable salt or solvate thereof, wherein thedosage form provides an in vitro release of ketamine, when measuredaccording to the USP Basket Method I in 0.1M HCl at 37° C. at 100 rpm,of 0 to 40% after 2 hours, of 10 to 70% after 4 hours, of 30 to 85%after 6 hours and of 45 to 100% after 8 hours, wherein the dosage formprovides an in vitro release of ketamine, when measured according to theUSP 1 Basket Method in 0.1M HCl at 100 rpm, after one hour at 37° C., inan aqueous solution containing 20% by volume of ethanol, in a ratio ofless than 2:1 relative to the amount of ketamine released, so measured,after one hour at 37° C. in an ethanol-free aqueous solution, whereinthe dosage form is a multi-particulate controlled release tablet,wherein the tablet comprises pellets each containing i) a corecomprising 1 to 30 wt. % inert beads, 5 to 400 mg and 1 to 40 wt. %ketamine hydrochloride, 0.01 to 10 wt. % binder, and 0 to 10 wt. %glidant, and ii) a release control layer comprising 1 to 40 wt. % of arelease control substance coated upon the core, wherein the releasecontrol substance is a water insoluble polymer, 0.01 to 10 wt % porebuilder, 0.01 to 10 wt. % plasticizer, and 0 to 15 wt. % glidant, andwherein the pellets are contained in an external phase comprisingcarboxymethyl cellulose, optionally in the form of a salt, as apharmaceutically acceptable excipient, 20 to 85 wt. % filler, 0 to 3 wt.% lubricant, and 0 to 5 wt. % glidant, wherein the tablet optionallycomprises an external film coating, and wherein all wt. % are based onthe total weight of the tablet, without the film coating.
 2. The oraldosage form according to claim 1, wherein the core comprises a layercomprising ketamine coated on an inert core.
 3. The oral dosage formaccording to claim 1, wherein the release control substance is an alkylcellulose.
 4. The oral dosage form according to claim 1, wherein thedosage form is administered once or twice daily.
 5. The oral dosage formaccording to claim 1, wherein the administration of a single oral dosageform leads in-vivo to a C_(max) of ketamine of 1 to 150 ng/ml and to aAUC_(0-∞) of 5 to 1000 h·ng/ml.
 6. The oral dosage form according toclaim 1, wherein T_(max) of ketamine is 3 to 9 h.
 7. The oral dosageform according to claim 1 having an absolute bioavailability F_(abs) of5 to 25%.
 8. A method for the treatment of neuropathic pain and to avoiddose dumping upon ingestion of alcohol, said method comprising orallyadministering the oral dosage form of claim 1 to a subject in needthereof.
 9. A method for the treatment of a patient suffering fromspinal cord injury, multiple sclerosis, cancer, immune mediateddisorders, a metabolic condition, herpes zoster infection, HIV-relatedneuropathies, nutritional deficiencies and to avoid dose dumping uponingestion of alcohol by the patient, said method comprising orallyadministering to the patient the oral dosage form of claim
 1. 10. Amethod for preparing an oral dosage form according to claim 1,comprising: a) coating inert cores with a layer comprising ketamine or apharmaceutically acceptable salt or solvent thereof, b) coating thecoated inert cores with a release-control layer comprising therelease-controlling substance, thus forming pellets, c) mixing thepellets with at least one pharmaceutically acceptable excipient, d)forming a tablet from the mixture comprising the pellets and the atleast one pharmaceutically acceptable excipient.
 11. The oral dosageform according to claim 1, wherein the release control substance isethylcellulose.
 12. The oral dosage form according to claim 1, whereinthe tablet comprises a break-line for facilitating its division in tointo two or more units.
 13. The oral dosage form according to claim 1,wherein ratio is less than 1.5:1.
 14. The oral dosage form according toclaim 1, wherein ratio is less than 1.2:1.
 15. A method of claim 9wherein the metabolic condition is diabetes.